Imatinib to Increase RUNX1 Activity in Participants With Germline RUNX1 Deficiency

* INCLUSION CRITERIA- AFFECTED PARTICIPANTS ONLY
* Affected participants must have a confirmed pathogenic or likely pathogenic germline RUNX1 variant by history. ClinGen expert variant curation panel criteria for pathogenicity will be utilized.
* Affected participants must have a history of clinically significant bleeding as defined by history of abnormal ISTH-BAT score, use of anti-bleeding medications (e.g., amicar), history of platelet transfusion, abnormal PFA screen, abnormal TEG, abnormal platelet aggregation or abnormal platelet electron microscopy.
* Bone marrow morphology, flow cytometry and cytogenetics confirmed by the NIH Department of Laboratory Medicine (DLM) at least within 12 months of initiating imatinib.
* TSO500 performed by NCI Lab of Pathology within 12 months of initiating imatinib.
* Substantial GI malabsorption is not suspected.
* Participants with human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial if their HAART medications do not interact with imatinib.
* Participants with evidence of chronic hepatitis B virus (HBV) infection, on suppressive therapy with undetectable HBV viral load are eligible for this trial. Suppressive therapy medication may not interact with imatinib.
* Participants with a distant history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with active HCV infection who are currently on treatment, with undetectable HCV viral load are eligible. If unknown HCV is detected upon screening- these participants will not be eligible for the study.

INCLUSION CRITERIA- UNAFFECTED PARTICIPANTS ONLY

* Unaffected family members or healthy volunteers without RUNX1 mutation by pedigree or molecular testing Only participants who are related to the proband need to provide a molecular test.
* The last dosage of any platelet inhibiting medications was at least 2 weeks prior to enrollment and research sample acquisition.

INCLUSION CRITERIA- ALL PARTICIPANTS

* Age \>=18 years.
* ECOG performance status \<=2 (Karnofsky \>=60%).
* Participants must have adequate organ and marrow function as defined below:

  * leukocytes \>= 3,000/mcL
  * absolute neutrophil count \>= 1,500/mcL
  * platelets \>= 50,000/mcL (without transfusion support)
  * total bilirubin within normal institutional limits or \<= 3 X the institutional upper limit of normal for participants with Gilbert s syndrome
  * AST(SGOT)/ALT(SGPT) \<= 2.5 X institutional upper limit of normal
  * creatinine within normal institutional limits OR creatinine clearance \>= 60 mL/min/1.73 m\^2 for participants with creatinine levels above institutional normal.

    * NIDDK CKD-EPI equation GFR = 141 x min (Scr /kappa, 1)\^alpha x max(Scr /kappa, 1)\^-1.209 x 0.993\^Age x 1.018 \[if female\] x 1.159 \[if black\] where: Scr is serum creatinine in mg/dL, kappa is 0.7 for females and 0.9 for males, alpha is -0.329 for females and -0.411 for males, min indicates the minimum of Scr /kappa or 1, and max indicates the maximum of Scr /kappa or 1.
    * Note: GFR is expressed in mL/min per 1.73 m\^2, Scr is serum creatinine expressed in mg/dL, age is expressed in years, kappa is 0.7 for females and 0.9 for males, alpha is -0.329 for females and -0.411 for males, min indicates the minimum of Scr /kappa or 1, and max indicates the maximum of Scr /kappa or 1. Race is self-identified.
* Women of child-bearing potential and men must agree to use effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 30 days after the last administration of study drug.
* Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 30 days after the last administration of study drug
* Ability of participant to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA- ALL PARTICIPANTS

* Participants who are receiving any other investigational agents.
* Participants who received prior hematologic malignancy directed therapy
* Participants receiving medication that would affect platelet number or function (e.g., aspirin and anti-platelet medications
* Participants without access to medical care at home.
* Pregnancy (confirmed with beta-HCG serum or urine pregnancy test performed in females of childbearing potential at screening).

EXCLUSION CRITERIA- AFFECTED PARTICIPANTS ONLY

* Participants with the following pathogenic/likely pathogenic abl mutations on baseline Illumina TSO500 testing of any detectable VAF within 12 months of receiving the first dose of imatinib

  --Abl mutations resistant to imatinib (T315I, F317L/V/C, T315A, V299L, Y253H, E255V/K, F359V/I/C)
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to imatinib or other agents used in study.
* Concomitant medications that include the following:

  --Participants requiring medications which are inhibitors or inducers of CYP3A4 metabolism, as these may change imatinib plasma levels.
* Uncontrolled intercurrent illness evaluated by history, physical exam, and chemistries or situations that would limit compliance with study requirements, interpretation of results or that could increase risk to the participant
* Participants with the following cardiac conditions: symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia.